The effectiveness and value of tezepelumab for severe asthma

DISCLOSURES: Drs Rind, Campbell, Pearson, Ms Herce-Hagiwara, Ms Fluetsch, and Ms Herron-Smith report grants from Arnold Ventures; Kaiser Foundation Health Plan, Inc; The Patrick and Catherine Donaghue Medical Research Foundation; Blue Cross Blue Shield of Massachusetts; and California Healthcare Foundation during the course of this study.


CLINICAL EFFECTIVENESS
Biologic therapies for asthma have typically reduced asthma exacerbations but have had smaller effects on the daily symptoms that interfere with the lives of people with severe asthma. Tezepelumab was evaluated in 2 randomized trials that included a broad population of patients with severe asthma. The treatment improved symptom scores compared with placebo, but these improvements (0.20 to 0.34) were smaller than the minimal clinically important differences of 0.5 on these scales. 7,8 In both trials, however, tezepelumab substantially reduced the annualized asthma exacerbation rate compared with placebo (rate ratio 0.29 to 0.44). 7,8 Reductions in exacerbations were found in patients with non-eosinophilic asthma; improvements in symptoms in non-eosinophilic asthma were only seen in 1 of the 2 trials. In patients with eosinophilic asthma, the benefits with tezepelumab seemed similar to those seen with another biologic, dupilumab. For patients with allergic asthma, improvements in symptoms with tezepelumab were similar to those found in older trials of omalizumab, whereas reductions in exacerbations were somewhat greater for tezepelumab than omalizumab.
In a separate randomized trial of tezepelumab in patients with steroiddependent asthma, patients treated with tezepelumab were not more likely to reduce their oral corticosteroid (OCS) dose at week 48 than patients treated with placebo (odds ratio [OR] = 1.28, 95% CI = 0.69-2.35). 9 In contrast, an earlier randomized trial of dupilumab found a greater reduction in OCS dose compared with placebo (70% vs 42%; P < 0.001), and more patients had a reduction of OCS dose of at least 50% (80% vs 50%; P < 0.001). 10 The effectiveness and value of tezepelumab for severe asthma In all trials, adverse events with tezepelumab did not appear to be significantly different from placebo. 7,8

Limitations of the Clinical Evidence
The lack of head-to-head trials limits the ability to compare tezepelumab with other biologics. This is a particular issue when trying to compare tezepelumab with the older trials of omalizumab. As with any biologic with a new mechanism of action, there are necessarily concerns about safety in the absence of longer-term data. Although asthma is more common in Black patients in the United States, Black patients were underrepresented in the trials of tezepelumab, raising potential concerns about the generalizability of the trial data in more diverse patient populations.

Economic Evaluation
We developed a Markov model to compare the cost-effectiveness of tezepelumab plus standard of care vs standard of care alone, based on models used in prior ICER reports. [11][12][13] The model included 3 primary health states: (1) an asthma nonexacerbation state (ie, day-to-day asthma symptoms), (2) an asthma exacerbation state (including 3 mutually exclusive subcategories: asthma-related event that requires an OCS burst, asthma-related emergency department visit, or asthma-related hospitalization), and (3) death (including asthma-related mortality and other-cause mortality).
The analysis used pooled efficacy data from the clinical trials to estimate results from a health care system perspective (ie, focusing on the direct medical care costs and health outcomes of the patient); a scenario analysis examined a modified societal perspective (ie, including patient productivity impacts, caregiver time, caregiver quality of life, and caregiver direct medical costs). Costs and outcomes were discounted at an annual rate of 3% over a lifetime time horizon.
Results from our analysis showed that at a placeholder annual price of approximately $28,000 (the net price of dupilumab; current annual wholesale acquisition costs for dupilumab and tezepelumab are approximately $42,000 and $47,000, respectively), 14 incremental cost-effectiveness ratios for tezepelumab were $430,000 per quality-adjusted life-year (QALY) gained and $422,000 per equal value lifeyear (evLY) gained; results were similar from the modified societal perspective. Additional results are presented in Table 1.
Sensitivity analysis demonstrated that the model was most sensitive to estimates of quality of life in the nonexacerbation health state and to the risk of death with a severe asthma exacerbation. In a probabilistic sensitivity analysis that jointly varied all model parameters over at least 1,000 simulations, no iterations resulted in an incremental cost-per-QALY result for tezepelumab at the placeholder price below the threshold of $150,000 per QALY gained or evLY gained.
ICER's analysis of the potential budget impact of tezepelumab at the placeholder price suggested that approximately 7% of 140,000 eligible patients could be treated each year over 5 years before crossing the ICER budget impact threshold of $734 million per year intended to represent the magnitude of budget impact that would have a disproportionate effect on affordability and access.

Limitations of the Economic Evaluation
The model was limited by the need to use a placeholder price based on the net price of dupilumab. Additionally, long-term evidence on response to treatment with tezepelumab, as well as long-term rates of discontinuation, were not available.

Policy Discussion
The

TABLE 1 Incremental Cost-Effectiveness Ratios Compared With Standard of Care for the Base Case
No value vote was taken at the public meeting because at the time of the meeting, the price of tezepelumab was not known.
The meeting concluded with a policy roundtable in which representatives from insurers and manufacturers, clinical experts, and patient representatives discussed how best to apply the evidence and additional considerations into clinical practice and into pricing and insurance coverage policies. The full set of policy recommendations can be found in the Final Evidence Report on the ICER website. The key policy recommendations are as follows: Recommendation 1: All stakeholders have a responsibility and an important role to play in ensuring that effective new treatment options for patients with severe asthma are introduced in a way that will help reduce health inequities. Recommendation 2: Payers will need to consider subpopulations of people with severe asthma when designing coverage policies for tezepelumab and other biologics.
Recommendation 3: Payers should recognize that step therapy has generally not been used for biologic therapy in asthma. Individual biologic therapies frequently fail and so all options using different mechanisms of action should be available to patients with asthma.
Recommendation 4: Biologic therapies for asthma are expensive and do not align reasonably with the magnitude of their clinical benefits; prices should be reduced. tezepelumab. The CEPAC is an independent appraisal committee composed of medical evidence experts, including practicing clinicians, methodologists, and patient engagement and advocacy leaders. Their deliberation included input from clinicians and patient representatives with asthma expertise, as well as public comments from drug manufacturers and the public.
Following the discussion, the panel members deliberated on key questions raised by ICER's report. The panel voted 10:4 that the available evidence was adequate to demonstrate that tezepelumab plus standard of care is superior to standard of care alone for adults and adolescents with severe asthma. The panel voted that the evidence was not adequate to distinguish the net health benefit of tezepelumab from dupilumab in eosinophilic asthma or steroid-dependent asthma or from omalizumab in allergic asthma.
The CEPAC also voted on other potential benefits and contextual considerations as part of a process intended to signal to policymakers whether there are important considerations when making judgments about long-term value for money not adequately captured in analyses of clinical effectiveness and/or cost-effectiveness. The results of these votes are shown in Table 2. They highlight several factors beyond the results of the cost-effectiveness analysis that the California Technology Assessment Forum panel felt were particularly important for judgments of overall longterm value for money.

TABLE 2 Votes on Other Benefits and Contextual Considerations
Recommendation 5: Researchers looking at real-world evidence in treatments of asthma should be aware of potential threats to validity, since given the likely small differences in efficacy of the agents, confounding or bias in the observational datasets could overwhelm any true estimates of effect.

Conclusions
Tezepelumab is effective in reducing exacerbations in a broad group of patients with severe asthma, including patients with non-eosinophilic asthma; patients with this subtype of severe asthma have not previously had an effective biologic therapy. New therapies are still needed that better improve daily symptoms in patients with severe asthma. In comparison with other available biologics, current evidence suggests that tezepelumab may be less effective than dupilumab in patients with steroid-dependent asthma.